Article: Aciclovir

Aciclovir
Systematic (IUPAC) name
2-amino-9-(2-hydroxyethoxymethyl)- 3H-purin-6-one
Identifiers
CAS number	59277-89-3
ATC code	J05AB01 D06BB03 S01AD03
PubChem	2022
DrugBank	APRD00567
Chemical data
Formula	C8H11N5O3
Mol. weight	225.21 g/mol
Pharmacokinetic data
Bioavailability	10–20% (oral)
Protein binding	9-33%
Metabolism	Viral thymidine kinase
Half life	2.2–20 hours
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	B3 (Au), B (U.S.)
Legal status	unscheduled/S4 (Au), POM (UK)
Routes	IV, oral, topical

Aciclovir (INN) (IPA: [eɪˈsaɪklovir]) or acyclovir (USAN, former BAN) is a guanine analogue antiviral drug used most commonly for the treatment of herpes simplex virus infection. It is one of the most commonly-used antiviral drugs, and is most commonly marketed under the trade name Zovirax (GSK).

Aciclovir was seen as the start of a new era in antiviral therapy, as it is extremely selective and low in cytotoxicity. Pharmacologist Gertrude B. Elion was awarded the 1988 Nobel Prize in Medicine partly for the development of aciclovir.

Pharmacology

Mechanism of action

Aciclovir differs from previous nucleoside analogues in that it contains only a partial nucleoside structure – the sugar ring is replaced by an open-chain structure. It is selectively converted into a monophosphate form by viral thymidine kinase, which is far more effective (3000 times) in phosphorylation than cellular thymidine kinase. Subsequently, the monophosphate form is further phosphorylated into the active triphosphate form, aciclo-GTP, by cellular kinases. Aciclo-GTP is a very potent inhibitor of viral DNA polymerase; it has approximately 100 times higher affinity to viral than cellular polymerase. Its monophosphate form also incorporates into the viral DNA, resulting in chain termination. It has also been shown that the viral enzymes cannot remove aciclo-GMP from the chain, which results in inhibition of further activity of DNA polymerase. Aciclo-GTP is fairly rapidly metabolised within the cell, possibly by cellular phosphatases.

Therefore, aciclovir can be considered a prodrug – it is administered in an inactive (or less active form) and is metabolised into a more active species after administration.

Microbiology

Aciclovir is active against most species in the herpesvirus family. In descending order of activity:^[1]

• Herpes simplex virus type I (HSV-1)
• Herpes simplex virus type II (HSV-2)
• Varicella zoster virus (VZV)
• Epstein-Barr virus (EBV)
• Cytomegalovirus (CMV)

Activity is predominately active against HSV, and to a lesser extent VZV. It is only of limited efficacy against EBV and CMV. It is inactive against latent viruses in nerve ganglia.

To date, resistance to aciclovir has not been clinically significant. Mechanisms of resistance in HSV include deficient viral thymidine kinase; and mutations to viral thymidine kinase and/or DNA polymerase, altering substrate sensitivity.^[2]

Pharmacokinetics

Aciclovir is poorly water soluble and has poor oral bioavailability (10–20%), hence intravenous administration is necessary if high concentrations are required. When orally administered, peak plasma concentration occurs after 1–2 hours. Aciclovir has a high distribution rate, only 30% is protein-bound in plasma. The elimination half-life of aciclovir is approximately 3 hours. It is renally excreted, partly by glomerular filtration and partly by tubular secretion.

Clinical use

Indications

Aciclovir is indicated for the treatment of HSV and VZV infections, including:^[3]

• Genital herpes simplex (treatment and prophylaxis)
• Labial herpes simplex (cold sores)
• Herpes zoster (shingles)
• Acute chickenpox in immunocompromised patients
• Herpes simplex encephalitis
• Acute mucocutaneous HSV infections in immunocompromised patients
• Herpes simplex keratitis

Dosage forms

Aciclovir is commonly marketed as tablets (200 mg and 400 mg), topical cream (5%), intravenous injection (25 mg/mL) and ophthalmic ointment (3%). Cream preparations are used primarily for labial herpes simplex. The intravenous injection is used when high concentrations of aciclovir are required. The ophthalmic ointment preparation is only used for herpes simplex keratitis.

Adverse effects

Systemic therapy

Common adverse drug reactions (≥1% of patients) associated with systemic aciclovir therapy (oral or IV) include: nausea, vomiting, diarrhoea and/or headache. In high doses, hallucinations have been reported. Infrequent adverse effects (0.1–1% of patients) include: agitation, vertigo, confusion, dizziness, oedema, arthralgia, sore throat, constipation, abdominal pain, rash and/or weakness. Rare adverse effects (<0.1% of patients) include: coma, seizures, neutropenia, leucopenia, crystalluria, anorexia, fatigue, hepatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis and/or anaphylaxis.^[3]

Additional common adverse effects, when aciclovir is administered IV, include encephalopathy (1% of patients) and injection site reactions. The injection formulation is alkaline (pH 11), and extravasation may cause local tissue pain and irritation.^[3] Renal impairment has been reported when aciclovir is given in large, fast doses intravenously, due to the crystallisation of aciclovir in the kidneys.

Topical therapy

Aciclovir topical cream is commonly associated (≥1% of patients) with: dry or flaking skin and/or transient stinging/burning sensations. Infrequent adverse effects include erythema and/or itch.^[3]

When applied to the eye, aciclovir is commonly associated (≥1% of patients) with transient mild stinging. Infrequently (0.1–1% of patients), opthalmic aciclovir is associated with superficial punctate keratitis and/or allergic reactions.^[3]

Toxicity

Since aciclovir can be incorporated also into the cellular DNA, it is a chromosome mutagen, therefore, its use should be avoided during pregnancy. However it has not been shown to cause any teratogenic nor carcinogenic effects. The acute toxicity (LD₅₀) of aciclovir when given orally is greater than 1 mg/kg, due to the low oral bioavailability. Single cases have been reported, where extremely high (up to 80 mg/kg) doses have been accidentally given intravenously without causing any major adverse effects.